Subtypes of familial breast tumours revealed by expression and copy number profiling

Abstract

Extensive expression profiling studies have shown that sporadic breast cancer is composed of five clinically relevant molecular subtypes. However, although BRCA1-related tumours are known to be predominantly basal-like, there are few published data on other classes of familial breast tumours. We analysed a cohort of 75 BRCA1, BRCA2 and non-BRCA1/2 breast tumours by gene expression profiling and found that 74% BRCA1 tumours were basal-like, 73% of BRCA2 tumours were luminal A or B, and 52% non-BRCA1/2 tumours were luminal A. Thirty-four tumours were also analysed by single nucleotide polymorphism-comparative genomic hybridization (SNP-CGH) arrays. Copy number data could predict whether a tumour was basal-like or luminal with high accuracy, but could not predict its mutation class. Basal-like BRCA1 and basal-like non-BRCA1 tumours were very similar, and contained the highest number of chromosome aberrations. We identified regions of frequent gain containing potential driver genes in the basal (8q and 12p) and luminal A tumours (1q and 17q). Regions of homozygous loss associated with decreased expression of potential tumour suppressor genes were also detected, including in basal tumours (5q and 9p), and basal and luminal tumours (10q). This study highlights the heterogeneity of familial tumours and the clinical consequences for treatment and prognosis.

Molecular insights on basal-like breast cancer

“…Several large and integrative research studies based on expression and copy number profiling of familial BC demonstrated molecular heterogeneity of these tumors similar to sporadic tumors, as well these studies defined molecular subtypes based on markers other than BRCA1 and BRCA2 germline status [11,43,44]. Microarray or immunohistochemical analyses demonstrated that approximately three quarters of BRCA1-related BC are BLBC whereas BRCA2 tumors generally cluster within the luminal A or B groups [43,44,45,46] and non-BRCA1/2 with luminal A tumors [11,44].…”

“…Microarray or immunohistochemical analyses demonstrated that approximately three quarters of BRCA1-related BC are BLBC whereas BRCA2 tumors generally cluster within the luminal A or B groups [43,44,45,46] and non-BRCA1/2 with luminal A tumors [11,44].…”

“…BRCA1-related BLBC are TN and frequently positive for Ki67, basal CKs (CK5/6, CK14), TP53, EGFR, P-cadherin [44,47] and with frequent X-chromosome abnormalities [6]. Interesting, the clinical outcomes for women with BLBC and BRCA1-related BC are broadly similar in particular for early (within 5 years) relapse and pattern of metastatic spread.…”

BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

“…Twosided independent Student's t test without equal variance assumption was used to determine p-values (*, P < 0.05; **, P < 0.01). For analysis of gene expression microarray in primary human breast tumors, box plots and dot plots were performed on three publicly available datasets of BRCA1 mutated breast tumors (van 't Veer et al, 2002;Jönsson et al, 2010;Waddell et al, 2010) and on three sporadic breast tumor datasets (Pawitan et al, 2005;Chin et al, 2006;Sabatier et al, 2011), respectively. Tumor subtype classification was determined as described in each study.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…For example, several observations may be expected to limit the efficiency of the PARP inhibition in BRCA1-and BRCA2-deficient tumors as a synthetic lethal approach. Increase in RAD51 Waddell et al, 2009) and HR can rescue growth defects in BRCA1-deficient cells . Furthermore, the depletion of 53BP1 can rescue BRCA1 deficiency by reactivation of ATM-dependent HR pathway (Bouwman et al, 2010;Bunting et al, 2010).…”